Ultrasonic and x-ray detectable biopsy site marker and apparatus for applying it

ABSTRACT

A biopsy site marker comprises small bodies or pellets of gelatin which enclose substantially in their interior a radio (X-ray) opaque object. The gelatin pellets are deposited into the biopsy site, typically a cylindrical opening in the tissue created by the recent use of a vacuum assisted large core biopsy device, by an applicator device that includes an elongated cylindrical body that forms a flexible tube and a piston slidable in the tube. One end of the tube is placed into the biopsy site. Typically, several gelatin pellets, only some of which typically do, but all of which may contain the radio opaque object, are deposited sequentially into the site through the tube. The radio opaque objects contained in the gelatin bodies are of a non-biological configuration and readily identifiable as man-made object, so that in observation by typical mammography equipment they do not assume the shape of a line, whereby they are readily distinguishable from granules and lines of calcification.

RELATED APPLICATIONS

This application is a continuation-in-part application to applicationSer. No. 09/241,936, filed on Feb. 2, 1999, now U.S. Pat. No. 6,161,034.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention is in the field of markers to be employed atbiopsy sites to permanently mark the site, and to methods and apparatusfor applying the permanent marker. More particularly, the presentinvention relates to a marker that is optimally adapted for markingbiopsy sites in human breast tissue with permanently placed markers thatare detectable by X-ray.

2. Brief Description of the Background Art

In modern medical practice small tissue samples, known as biopsyspecimens, are often removed from tumors, lesions, organs, muscles andother tissues of the body. The removal of tissue samples may beaccomplished by open surgical technique, or through the use of aspecialized biopsy instruments such as a biopsy needle. A well knownstate-of-the-art instrument that is often used in connection with thepractice of the present invention is known as the “vacuum assisted largecore biopsy device”.

After a tissue sample has been removed, it is typically subjected todiagnostic tests or examinations to determine cytology, histology,presence or absence of chemical substances that act as indicators fordisease states, or the presence of bacteria or other microbes. The abovementioned and other diagnostic tests and examinations per se are wellknown in the art and need not be described here. It is sufficient tonote that the information obtained from these diagnostic tests and/orexaminations is often of vital importance for the well-being of thepatient and is used to make or confirm diagnoses and often to formulatetreatment plans for the patient. As is known, obtaining a tissue sampleby biopsy and the subsequent examination are frequently, almostinvariably, employed in the diagnosis of cancers and other malignanttumors, or to confirm that a suspected lesion or tumor is not malignant,and are frequently used to devise a plan for the appropriate surgicalprocedure or other course of treatment.

Examination of tissue samples taken by biopsy, often by theabove-mentioned “vacuum assisted large core biopsy sampler” is ofparticular significance in the diagnosis and treatment of breast cancerwhich is the most common cancer suffered by women in the U.S.A andelsewhere in the industrially developed world. Proper diagnosticprocedures, frequent examination by well known techniques such as“mammography” and prompt subsequent surgical treatment have, however,significantly reduced the mortality rate caused by this form of cancer.For this reason, in the ensuing discussion of the pertinent backgroundart and in the ensuing description the invention will be described asused for marking biopsy sites in human and other mammalian breast,although the invention is suitable for marking biopsy sites in otherparts of the human and other mammalian body as well.

Thus, as is known, when an abnormal mass in the breast is found byphysical examination or mammography a biopsy procedure follows almostinvariably. The nature of the biopsy procedure depends on severalfactors. Generally speaking, if a solid mass or lesion in the breast islarge enough to be palpable (i.e., felt by probing with the fingertips)then a tissue specimen can be removed from the mass by a variety oftechniques, including but not limited to open surgical biopsy or atechnique known as Fine Needle Aspiration Biopsy (FNAB). In opensurgical biopsy, an incision is made and a quantity of tissue is removedfrom the mass for subsequent histopathological examination. In the FNABprocedure, a small sample of cells is aspirated from the mass through aneedle and the aspirated cells are then subjected to cytologicalexamination.

If a solid mass of the breast is small and non-palpable (e.g., the typetypically discovered through mammography), a relatively new biopsyprocedure known as “stereotactic needle biopsy” may be used. Inperforming a stereotactic needle biopsy of a breast, the patient lies ona special biopsy table with her breast compressed between the plates ofa mammography apparatus and two separate digital x-rays are taken fromtwo slightly different points of view. A computer calculates the exactposition of the lesion with X and Y coordinates as well as depth of thelesion within the breast. Thereafter, a mechanical stereotacticapparatus is programed with the coordinates and depth informationcalculated by the computer, and such apparatus is used to preciselyadvance the biopsy needle into the small lesion. Usually at least fiveseparate biopsy specimens are obtained from locations around the smalllesion as well as one from the center of the lesion.

After the biopsy sample is taken, it may take several days or even aweek before the results of the examination of the sample are obtained,and still longer before an appropriate treatment decision is reached. Ifthe decision involves surgery it is clearly important for the surgeon tofind the location in the breast from where the tumor tissue has beentaken in the biopsy procedure, so that the entire tumor and possiblysurrounding healthy tissue can be removed. For example, the particulartreatment plan for a given patient may require the surgeon to remove thetumor tissue and 1 centimeter of the tissue surrounding the tumor. Aco-pending application for United States Letters Patent by the sameinventors discloses markers which are particularly well adapted formarking biopsy sites in the human breast, and which markers remaindetectable by X-ray, ultrasound or some other detection technique onlyfor a given time period (i.e. for 6 months) and slowly disappearthereafter, for example by absorption into the body. The purpose of suchmarkers is to facilitate the surgical procedure that is performed whilethe marker is still detectable. The disappearance of the marker after alonger period of time may be advantageous to avoid obscuring orinterfering with follow-up studies or further mammography or otherimaging studies.

In connection with the background art the following specific printed artis mentioned. U.S. Pat. Nos. 2,192,270 and 5,147,307 describe visuallydiscernible markers that are applied externally to the patient's skin.Radiographically (X-ray) detectable tissue markers (e.g., clips orstaples) that are attached to tissue adjacent to the site from which thebiopsy specimen has been removed, are described in International PatentPublication No. WO 98/06346. Radiographically visible markers (e.g.marker wires) that may be introduced into the biopsy site and areinserted through the biopsy needle after a tissue sample is removed andwhich are thereafter allowed to remain protruding from the patient'sbody, are also described in WO 98/06346. However, due to the consistencyof breast tissue and the fact that these biopsy site markers aretypically introduced while the breast is still compressed between themammography plates, these biopsy markers of the prior art may becomeattached to adjacent bands of connective tissue that do not remain atthe specific location of the biopsy after the breast has beendecompressed and removed from the mammography apparatus, and may sufferfrom additional disadvantages as well.

Thus, there is still a need in the art for of biopsy site markers thatare deliverable into the cavity created by removal of the biopsyspecimen and not into tissue that is located outside of that biopsycavity, and which will not migrate from the biopsy cavity even when thebreast tissue is moved, manipulated or decompressed. Moreover, suchdesired markers should remain detectable at the biopsy site i. e. withinthe biopsy cavity for an indefinite time period, and still should notinterfere with imaging of the biopsy site and adjacent tissues at alater point of time, and most importantly should be readilydistinguishable in the various imaging procedures from lines ofcalcifications which frequently are signs for a developing malignancy.The present invention provides such permanent biopsy site markers aswell as apparatus and method for delivering such markers into the biopsycavity.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide a biopsy site markerthat is deliverable into the cavity created by removal of the biopsyspecimen.

It is another object of the present invention to provide a biopsy sitemarker that does not migrate from the biopsy cavity even when thesurrounding tissue is moved, manipulated or decompressed.

It is still another object of the present invention to provide a biopsysite marker that meets the foregoing requirements and that remainsdetectable at the biopsy site for an indefinite period of time.

It is yet another object of the present invention to provide a biopsysite marker that meets the foregoing requirements and that is readilydistinguishable by X-ray from granules or lines of calcifications whichfrequently are signs for a developing malignancy.

It is a further object of the present invention to provide an apparatusand method for placing into the biopsy cavity a biopsy site marker thatmeets the foregoing requirements.

These and other objects and advantages are attained by a biopsy sitemarker that comprises small bodies or pellets of gelatin which enclosesubstantially in their interior a radio (X-ray) opaque object. Thegelatin pellets are deposited into the biopsy site, typically acylindrical opening in the tissue created by the recent use of a vacuumassisted large core biopsy device, by injection from an applicatorthrough a tube that is placed into the biopsy site. Typically, severalgelatin pellets, only some of which typically do, but all of which maycontain the radio opaque object, are deposited sequentially from theapplicator into the site through the tube. The radio opaque objectscontained in the gelatin bodies have a non-biological shape orconfiguration to be identifiable as a man-made object such that inobservation by typical mammography equipment, that is when viewed fromat least two different viewing angles, they do not assume the shape of aline, whereby they are readily distinguishable from granules or lines ofcalcification.

The features of the present invention can be best understood togetherwith further objects and advantages by reference to the followingdescription, taken in connection with the accompanying drawings, whereinlike numerals indicate like parts.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a perspective view of a preferred embodiment of the biopsysite marker of the present invention.

FIG. 2 is a perspective view of a plurality of biopsy site markers inaccordance with the first embodiment of the present invention.

FIG. 3 is a perspective view of an applicator apparatus in accordancewith the present invention, for depositing the biopsy site marker at abiopsy site.

FIG. 4 is a perspective view of the applicator apparatus of FIG. 3,showing the applicator with an extended piston indicating that theapplicator is loaded with biopsy site markers.

FIG. 5 is a cross-sectional view of the site marker shown in FIG. 4, thecross section taken on lines 5,5 of FIG. 4.

FIG. 6 is an enlarged cross sectional view showing the applicator ofFIG. 4 loaded with biopsy site markers in accordance with the presentinvention.

FIG. 7 is a schematic view of a human breast, showing a biopsy cavity ofthe type obtained by a vacuum assisted large core biopsy sampler, intowhich a plurality of biopsy markers are deposited in accordance with thepresent invention.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The following specification taken in conjunction with the drawings setsforth the preferred embodiments of the present invention. Theembodiments of the invention disclosed herein are the best modescontemplated by the inventors for carrying out their invention in acommercial environment, although it should be understood that variousmodifications can be accomplished within the parameters of the presentinvention.

Referring now to the drawing figures and particularly to FIGS. 1 and 2,a body 20 of gelatin or reconstituted collagen in the shape of a pelletthat includes or incorporates a radio-opaque marker 22 of a definiteshape is disclosed. The gelatin or reconstituted collagen body 20 can beof virtually any shape or configuration, however the herein shown shapeof a cylinder or pellet is preferred. The gelatin body of pellet 20 isof such size that several of the pellets can be deposited in a biopsysite, such as a typical biopsy site obtained by using the vacuumassisted large core biopsy device that is frequently used in currentmedical practice. The gelatin body or pellet 20 is stored and isapplied, that is deposited in the biopsy site, in a dehydrated formthrough an applicator device that forms another aspect of thisinvention. However, when the gelatin body or pellet 20 of the inventionis not deposited through the applicator device, it does not necessarilyneed to be stored and applied in a dehydrated form. Nevertheless,storing the gelatin pellets 20 in dehydrated form increases their usefulshelf-life and renders it easier to keep them sterile.

After having been deposited at the biopsy site the gelatin marker 20slowly absorbs moisture from the surrounding tissue and becomeshydrated. In the dehydrated form, shown in the appended drawing figures,the gelatin body or pellet 20 is approximately 1 to 3 mm in diameter andis approximately 5 to 10 mm long. The presently preferred embodiment ofthe gelatin pellet 20 is approximately 2 mm in diameter and isapproximately 8 mm long. After the pellet 20 has reached hydrationequilibrium with the surrounding tissue it becomes approximately 3 to 5mm in diameter and approximately 10 to 15 mm long. After hydration thepresently preferred embodiment of the pellet 20 is approximately 4 mm indiameter and approximately 10 mm long.

The gelatin or reconstituted collagen material itself is observed underultrasound examination as a white spot because of the air pocketsusually entrapped in its matrix. In mammography the gelatin is observedas dark spots in normal breast, because of the presence of the airpockets. In a fatty breast viewed by mammography the gelatin marker isobserved as a lighter area containing dark spots, due to the water inthe hydrated gelatin absorbing more energy than the surrounding matrixand the air pockets within the matrix. A pellet 20 or plurality ofpellets 20 due to their bulk may also be palpable and locatable bytactile means within the breast tissue or other tissue. The gelatin orreconstituted collagen marker itself can be made even more radio-opaqueby ion-impregnation and chelation techniques which are described indetail in the aforesaid co-pending application Ser. No. 09/241,936 filedon Feb. 2, 1999 by the same inventors in connection with the descriptionof biopsy markers of that application, and the description of thismethod of rendering the gelatin markers radio-opaque is also providedhere below. The disclosure of co-pending application Ser. No. 09/241,936is incorporated herein by reference in its entirety. The gelatin orreconstituted collagen material can also be made more radio-translucentby entrapping (mixing) a substantial amount of air in the gelatin.Moreover, a visually detectable substance, such as carbon particles, ora suitable dye (e.g. methylene blue or indigo) may also be added to thegelatin to make the marker visible by a surgeon during dissection of thesurrounding breast tissue.

The gelatin or reconstituted collagen per se does not serve as apermanent marker of the biopsy site because it is eventually reabsorbedby the body, although the dye or even ionic material that made thegelatin visible or radio-opaque, respectively, may remain at the sitefor longer time period than the palpable gelatin pellet, and may remainthere indefinitely. Factors which influence how long the gelatin orreconstituted collagen pellet remains at the site, and various means toadjust this time period are described in the aforementioned co-pendingapplication Ser. No. 09/241,936.

It is a novel and important aspect of the present invention toincorporate into the gelatin or reconstituted collagen body or pellet 20the radio-opaque marker 22. The radio-opaque or X-ray detectable marker22 that is incorporated or enclosed in the gelatin pellet 20 must havethe following properties. First, by its very nature it must bedetectable by X-ray, including the type of radiography used in thepractice of mammography. It must be comprised of a material orcomposition that is not absorbed by the body and stays for indefinitetime at the biopsy site, retains its shape and remains X-ray detectableat the biopsy site also for an indefinite time. The material orcomposition of the radio-opaque marker 22 must, of course, bebiocompatible at the site where it is deposited. Another importantrequirement is that the biocompatible marker must have an identifiablespecific non-biological shape or form. The purpose of specific form forthe marker is to render the marker distinguishable under X-ray or in amamographic examination from naturally formed calcification granules ora line of such granules, which are also X-ray opaque. As is known, aline of calcification which normally forms along ducts is considered asign of developing malignancy. Thus, the marker 22 should be of suchspecific configuration that when it is viewed sterically, as during amammography examination, it should be distinguishable from an X-rayopaque line. Numerous specific shapes or configurations satisfy theforegoing requirements, however amorphous X-ray opaque material thatwould be uniformly (or substantially uniformly) distributed in thegelatin pellet 20 is unlikely to satisfy these requirements.

Materials or compositions which are suitable for the marker 22 includemetal, such as stainless steel, tantalum, titanium, gold, platinum,palladium, various alloys that are normally used in bioprosthesis andceramics and metal oxides that can be compressed into specific shapes orconfigurations. Among these the use of biocompatible metals is presentlypreferred, and the herein described preferred embodiment of the marker22 is made of stainless steel. Generally speaking the marker 22 isapproximately 0.010 to 0.060 inches wide, approximately 0.030 to 0.200″long and approximately 0.002 to 0.020″ thick. The presently preferredpermanent marker 22 shown in the drawing figures has the configurationor shape approximating an upside down turned Greek letter gamma (γ), isapproximately 0.10″ long and approximately 0.040″ wide. The upside-downGreek letter gamma (γ) shape is believed to be unique, has someresemblance to the popular breast cancer awareness ribbon and is readilydistinguishable under X-ray and mammography as a “man-made” markerobject from any naturally formed X-ray opaque body. Variousmanufacturing techniques which per se are well known in the art, can beutilized to manufacture the X-ray opaque permanent marker 22. Thus, themarker 22 can be formed from wire, or can be electrochemically etched orlaser cut from metal plates. The presently preferred embodiment of thegamma (γ) shaped marker 22 is formed by electrochemical etching fromstainless steel plates.

FIGS. 1, 2 and the other drawing figures, as applicable, show only onemarker in the gelatin pellet 20, although more than marker may beincorporated in the pellet 20. FIG. 1 discloses a cylindrically shapedgelatin pellet 20 that in accordance with the present invention includesthe gamma (γ) shaped stainless marker 22, and as an optional featurealso includes a dye or other coloring material (e.g. indigo) that alsostays substantially permanently at the biopsy site and is visible by asurgeon when the breast tissue is dissected, as in an operation wheretumor tissue is removed (lumpectomy). Gelatin bodies or pellets 20 allof which include one or more permanent radio opaque markers 22 inaccordance with the present invention may be deposited at a biopsy site.Alternatively, a series of gelatin bodies or pellets 20 where only somebut not all include a permanent X-ray opaque marker 22 of uniquenon-biological shape, may be deposited at the biopsy site. Preferably, aseries of pellets 20 are deposited where each second, each third, oreach fourth etc., pellet includes the marker 22. FIG. 2 discloses anexample of a series or sequence of pellets 20 where each second pellet20 includes the metal marker 22 and where each pellet 20 that does notinclude the metal marker 22 includes carbon black or dye that is visibleto the surgeon during operation. In this connection it should beunderstood and appreciated that as noted above the gelatin bodies orpellets 20 themselves serve a purpose of marking the biopsy site for apredetermined length of time, that is until they become absorbed by thebody.

The drawing figures, particularly FIGS. 1 and 2 show the metal marker 22disposed substantially in the center of the cylindrical gelatin pellet20. This is preferred but is not necessary for the present invention.The metal marker 22 can be embodied in or included in the gelatin body20 virtually anywhere. The gelatin body or pellet 20 however has to havesufficient integrity or firmness to retain the metal marker 22 and airbubbles which are usually deliberately entrapped in the gelatin. As isknown, the firmness or bodily integrity of gelatin is measured in unitsof Bloom. Generally speaking it was found in accordance with the presentinvention that the higher the Bloom strength of the gelatin used in themarker 20 the better the marker performs. The higher Bloom strengthgelatin holds gas bubbles within its matrix better than lower Bloomstrength gelatin. Gelatin with a Bloom strength of approximately 150especially 175 is adequate for the practice of the present invention,but a more preferred range is 200 to 300 Bloom, the most preferred rangebeing between 250 and 300. (For comparison, typical food gelatin isapproximately 75 Bloom, and gelatin of 300 Bloom feels like a softrubber eraser.)

A description how to obtain gelatin or reconstituted collagen bodiessuitable for use as markers 20 with various properties, before thepermanent radio-opaque metal or like marker 22 of specific form isincorporated therein, is provided below in connection with followingexamples.

EXAMPLE OF RADIOGRAPICALLY VISIBLE/PALPABLE MARKER MATERIAL FORMED OFMETAL IONS IN COMBINATION WITH A COLLAGENOUS OR GELATINOUS MATRIX

U.S. Pat. No. 4,847,049 (Yamamoto incorporated herein by reference)describes an ion-impregnation or chelation technique whereby an ion maybe impregnated or chelated to collagen for the purpose of impartingantimicrobial properties to the collagen preparation. Thus, using thistechnique, imageable ions such as radiographically visible metal ions,may be bound to a bulky collagenous material to form a marker 10 thatmay be a) imaged by radiographic means and b) located by palpation oftissue surrounding the biopsy site. For example, a silver ion-renaturedcollagen composition may be prepared by the following process:

Step 1—Renaturation of Collagen (or Gelatin)

Collagen may be renatured to an insoluble form by processing ofdenatured collagen that has been obtained from a natural source such asbovine corium (hide), bovine tendon, and porcine skin. Alternatively,pre-processed, insoluble collagen may be purchased in the form of acommercially available hemostatic material such as Collastat™ andAvitene™ nonwoven web. Methods for renaturing collagen are known in theliterature, including, for example, those methods described in U.S. Pat.Nos. 4,294,241 and 3,823,212. The specifications of U.S. Pat. Nos.4,294,241 and 3,823,212 are incorporated herein by reference.

A particularly preferred form of renatured collagen for utilization inaccordance with the present invention is one that has been renatured andcovalently cross-linked. This collagen may be prepared by utilizingreadily available polyfunctional cross linking agents or fixatives, suchas dialdehydes, dicarboxylic acids, diamines, and the like. Typically,tropocollagen is dissolved in a buffer of pH 3.0 to 5.0 to provide asolution containing approximately 1 to 2% by weight of the collagen.Then 1% of a dialdehyde cross-linking agent such as glutaraldehyde orformaldehyde is then added. The mixture is then frozen and stored forapproximately 24 hours. After thawing and washing to remove unreactedcross linking agent, the renatured cross-linked collagen is then readyfor contact with a silver ion-containing solution.

Step 2—Binding of Metal Ions to the Renatured Collagen

The source of silver ion may be a water soluble silver salt, preferablysilver nitrate. While the concentration of the silver ion in thesolution is not particularly critical, it will be usually convenient toutilize solutions in the concentration range of about 10 to 10millimolar.

The renatured collagen is preferably contacted with a silverion-containing solution in the pH range of about 4 to 9. The pH of thesilver ion-containing solution can be controlled by the addition of anappropriate titrating agent, such as nitric acid, or potassiumhydroxide, as required, to maintain the pH at less than about 9.0 toavoid the degradation of the silver. There is not believed to be anylower limit for the pH, however, normally a pH above 4.0 will beconvenient. A particularly preferred range for the pH is from 7.0 to7.5. The binding capacity of silver by collagen is particularlyeffective within this preferred pH range, although the amount of bindingby silver by the collagen is further controllable by the concentrationof the silver ion-containing solution and/or exposure time of thecollagen to the silver ion-containing solution. Simultaneous with orsubsequent to exposure of the collagen to the silver ion-containingsolution, the collagen is then exposed to ultraviolet radiation ofenergy and duration sufficient to strengthen the binding of the silverions to the collagen without substantial formation of metallic silverformed as a result of oxidation of various functional groups in thecollagen by the silver ion. While the exact limits of the ranges of theconditions which will be sufficient to strengthen the binding of thesilver ions without substantial formation of metallic silver are notprecisely determinable, it will generally suffice to maintain the pH ofthe silver-collagen environment at less than 8.0 while exposing thecollagen to ultraviolet radiation in the range of about 210 to 310 nmwavelength for about from 5 to 15 minutes. The time of UV exposure forcomplete reaction is inversely proportional to the light intensity whichis preferably in the range of 100 to 1,000 microwatts/cm². A slightcoloration of the collagen due to the exposure to ultraviolet radiationis acceptable, i.e., a turning from white to a light brown to yellowcolor, indicating a slight oxidation reaction occurring in the collagen,however, the radiation should not be to the extent that dark brown orblack areas in the collagen occur due to over-oxidation and/orsubstantial formation of metallic silver. Normally the exposure will beperformed at ambient temperatures, i.e., in the range of about 20degrees to 25 degrees C., however, there is not believed to be anyreason why the exposure could not occur at higher or lower temperaturesproviding that the temperature is not high enough to cause degradationof the collagen and/or silver ion. There is not believed to be any lowerlimit to the temperature at which the exposure may take place, providedit is above the freezing point of the ion-containing solution.Ultraviolet radiation may be provided by any conventional ultravioletradiation source of appropriate wavelength, such as germicidal lamps andmercury/xenon lamps.

Step 3 (Optional)—Addition of Visible Marker Component to the Collagenor Gelatin Matrix

If it is desired for the marker to be detectable visually, as well as byimaging and palpation, a quantity of a visible substance having a colordissimilar blood or tissue may be added. For example, carbon particlesor a dye (e.g., methylene blue, indigo) may be added to theabove-prepared silver ion/collagen preparation to provide a coloredsilver ion/collagen marker 10 that is imageable (by radiographic means),palpable (by hand) and visible (under white light in the operatingroom).

The above-described collagen-metal ion marker 10 (with or withoutvisible marker component) is introduced into the cavity created byremoval of the biopsy specimen. The quantity of this marker 10introduced may be sufficient to distend or stretch the biopsy cavitysomewhat, thereby creating a more palpable and obvious mass of markermaterial at the biopsy site.

Renatured gelatin or a cross-linked gelatin preparation such as Gelfoam™may be impregnated or combined with a metal ion to provide agelatin-metal ion marker material. The gelatin may be prepared andion-bound by the same method as set forth hereabove for collagen.

EXAMPLE OF RADIOGRAPHICALLY OR ULTRASONICALLY VISIBLE/PALPABLE MARKERMATERIAL FORMED OF A GAS IN COMBINATION WITH A COLLAGENOUS OR GELATINOUSMATRIX

Step 1—Renaturation of Collagen (or Gelatin)

Collagen or gelatin is renatured, as by the method described in Step 1of the immediately preceding example and described in the literature,including, for example, those methods described in U.S. Pat. Nos.4,294,241 and 3,823,212.

Step 2—Dispersing of Air or Other Gas in the Renatured Collagen orGelatin Matrix

Air or another biologically inert gas (e.g., carbon dioxide) is thendispersed throughout the renatured collagen or gelatin matrix by asuitable means such as mixing, mechanical blending, nucleation,bubbling, etc. This results in the formation of many small gas bubblesthroughout the collagenous or gelatinous matrix and provides a markersubstance that can be introduced into the biopsy cavity through acannula or tube and is substantially more radio-lucent than the tissuesurrounding the biopsy cavity. In this regard, this marker can be imagedby x-ray or ultrasound but will not block or obscure imaging of tissuethat lies immediately adjacent the biopsy cavity. Also, because of thebulk of the collagen or gelatin matrix, the marker is readily palpableand locatable by tactile means within the surrounding breast tissue orother tissue.

Step 3 (Optional)—Addition of Visible Marker Component

If it is desired for the marker to be detectable visually, as well as byimaging and palpation, a quantity of a visible substance having a colordissimilar to blood or tissue may be added. For example, carbonparticles or a dye (e.g., methylene blue, indigo) may be added to theabove-prepared silver ion/collagen preparation to provide a coloredsilver ion/collagen marker 10 that is imageable (by radiographic means),palpable (by hand) and visible (under white light in the operatingroom).

In routine use, the above-described collagen/gas or gelatin/gas marker10 (with or without visible marker component) is introduced into thecavity created by removal of the biopsy specimen. The quantity of thismarker 10 introduced may be sufficient to distend or stretch the biopsycavity somewhat, thereby creating a more palpable and obvious mass ofmarker material at the biopsy site.

PREFERRED EXAMPLE OF PREPARING CYLINDRICALLY SHAPED GELATIN PELLETS 20HAVING A COLORANT AND INCLUDING THE PERMANENT MARKER 22

80 grams of dry gelatin obtained from porcine skin is mixed into 1000 mlof hot water (180° F.). Variations in gelatin to water ratio will changethe consistency but are nevertheless permissible within the scope of theinvention. The 80 grams of gelatin is about the maximum amount whichwill dissolve in water without modifications to pH. The gelatin is thenfully dissolved in the water with slight mixing. In a separatecontainer, 1.6 grams of indigo colorant is mixed into 20 ml of ethylalcohol. Then the ethanol solution of the colorant is added by mixing togelatin dissolved in water. Air is then whipped into gelatin mixture tofroth the mixture.

The gelatin dissolved in water is then poured into molds (not shown)which have the shape of the desired gelatin body. In the preferredembodiment the mold is shaped to provide the cylindrical pellet shown inthe drawing figures. One gamma (γ) shaped permanent marker 22, made bychemical etching from stainless steel plates, is deposited into thegelatin in each mold. (In alternative embodiments more than one marker22 may be deposited into each mold.) Due to the viscosity of the gelatinsolution the marker 22 does not usually sink to the bottom of the mold.The top of the plate (not shown) holding a plurality of molds issqueegeed to level the mixture.

After cooling to approximately 40° F. or cooler temperature the gelatinsets and provides the gelatin body 20 that incorporates the permanentmarker 22 However, in order to dehydrate the marker it is first frozenand thereafter lyophilized in commercial lyophilization apparatus.Gelatin pellets containing the permanent marker 22 but not having acolorant can be prepared in the same manner, but without adding indigodye or other colorant. Gelatin bodies or markers 20 that do not includeor incorporate a permanent marker 22 can also be made in this manner,but without depositing the marker 22 into the gelatin after it has beenplaced into the mold. The gelatin body 20 prepared in this manner isreabsorbed from the biopsy site by the human body in approximately threeweeks, whereas the permanent marker 22 remains indefinitely.

DESCRIPTION OF THE APPLICATOR APPARATUS AND ITS USE IN CONJUNCTION WITHTHE BIOPSY MARKER OF THE INVENTION

Referring now to FIGS. 3-7 the applicator device or apparatus 24 withwhich the biopsy markers of the invention are preferably applied ordeposited, is disclosed. In this connection it should be understood thatthe biopsy markers of the invention can be used without the applicator,and can be deposited in accordance with the various methods andtechniques utilized in the state-of-the-art. However, a preferredtechnique of applying the biopsy markers of the invention is to place ordeposit them in a biopsy cavity that is obtained with a vacuum assistedlarge core biopsy device of the type presently used in thestate-of-the-art. Such a device, distributed for example by Johnson andJohnson Endo Surgery is well known in the art, and is schematicallyshown in FIG. 7.

The applicator 24 of the invention comprises an elongated cylindricalbody 26 having an interior cavity and a piston 28 that fits and slidesback and forth in the elongated cylindrical body 26. The cylindricalbody 26 has an enlarged disk 30 at one end 32. The disk 30 serves torender it convenient for a user (not shown) to operate the applicator24, as is described below. The cylindrical body 26 that can also bedescribed as an elongated flexible tube has an opening 34 that commencesa relatively short distance, that is approximately 0.3″ before itsother, closed end 36. The opening 34 is configured to form a ramp in theside of the tube 26. The outer diameter of the tube 26 is such that itfits through the vacuum assisted large core biopsy device 38 shown inFIG. 7. In this connection it should of course be understood that theprecise dimensions of the tube 26 are coordinated with the dimensions ofthe piston 28 and with the vacuum assisted large core biopsy device 38.Moreover, the diameter of the gelatin pellets 20 in their dehydratedform are also coordinated with the inner diameter of the cylinder ortube 26. The cylinder or tube 26 and the piston 28 can be made from anyappropriate medical grade plastic material, and is preferably made ofhigh density polyethylene. The outer diameter of the presently preferredembodiment of the cylinder or tube 26 is approximately 0.093″ and itsinner diameter is approximately 0.070″.

In the preferred manner of using the biopsy markers of the presentinvention having the permanent markers 22 incorporated in a gelatin body20, as well as using biopsy markers that have only the gelatin body 20without a permanent marker 22, the applicator device 24, more preciselythe tube 26 is loaded with a desired number of pellets 20, as is shownin FIGS. 4-6. Any number of pellets 20 within the range of 1 toapproximately 30 may be loaded within the tube 26, however presently itappears that approximately 8 pellets 20 are optimal for being loadedinto the tube 26 and to be deposited in a biopsy cavity whereapproximately 1 gram of tissue had been removed. Such a biopsy cavity 40in a human breast 42 is schematically illustrated in FIG. 7. The pellets20 which are loaded into the applicator tube 26 may all include thepermanent marker 22, but it is presently preferred that only every otherpellet 20 loaded into the applicator tube 26 have the permanent marker22. Such an array of 8 pellets 20, alternating between pellets with andwithout permanent markers 22 is shown in FIG. 2.

When the pellets 20 are in the tube 26 the piston 28 is extended, as isshown in FIGS. 4 and 5. The pellets 20 are expelled one-by-one from thetube 26 through the ramp-shaped opening 34 as the piston 28 is pushedinto the cylinder or tube 26. During this process the closed end 36 ofthe tube 26 is disposed in the cavity 40 formed by biopsy sampling. Itis contemplated that the dispersed radio-opaque permanent markers 22provide a good definition of the entire biopsy cavity 40 for subsequentobservation or surgical procedure. FIG. 3 illustrates the applicatordevice 24 after the pellets 20 have been expelled from the applicatortube 26.

What is claimed is:
 1. A marker body which is deliverable to a biopsysite within a patient, comprising a preshaped pellet formed ofbioabsorbable material having a plurality of gas bubbles dispersedtherein which are configured to facilitate ultrasonic observation of thepellet at the biopsy site within the patient, and having an X-raydetectable element of specific predetermined non-biologicalconfiguration embedded therein.
 2. A marker body in accordance withclaim 1 wherein the X-ray detectable element of specific predeterminednon-biological configuration comprises metal.
 3. A marker body inaccordance with claim 2 wherein the X-ray detectable element of specificpredetermined non-biological configuration comprises stainless steel. 4.A marker body in accordance with claim 2 wherein the X-ray detectableelement of specific predetermined non biological configuration isconfigured substantially in a shape of a Greek letter gamma (γ).
 5. Amarker body in accordance with claim 2 wherein the X-ray detectableelement consists essentially of an electrochemically etched stainlesssteel element.
 6. A marker body in accordance with claim 1 wherein thebody of bioabsorbable material is configured in the shape of a cylinder.7. A marker body in accordance with claim 1 wherein the pellet is about1 to about 3 mm in diameter and is about 5 to about 10 mm long.
 8. Amarker body in accordance with claim 7 wherein the bioabsorbablematerial has a Bloom rating in the range between about 150 to about 300Bloom.
 9. A marker body in accordance with claim 1 wherein thebioabsorbable material is gelatin.
 10. A marker body in accordance withclaim 1 wherein the pellet is approximately 2 mm in diameter and isapproximately 8 mm long.
 11. An applicator device for a biopsy sitemarker, the device comprising: an elongated cylindrical body that formsa flexible tube and includes a cylindrical cavity having an internallumen, an open end and a closed end and a ramp within the internal lumenleading to a side opening in the flexible tube in proximity of theclosed end; and a piston that is moveable back and forth in thecylindrical cavity forming the tube, the tube being configured to beloaded in the internal lumen with a plurality of biopsy site markerbodies according to claim 1 said marker bodies being disposed betweenthe end of the piston and the side opening when the piston is extendedoutwardly from the cylindrical cavity.
 12. An applicator device inaccordance with claim 11 wherein the elongated cylindrical body has aninternal diameter of approximately 0.070″.
 13. In combination: anapplicator tube having an internal lumen, an open end and a closed endand a ramp shaped opening in proximity of the closed end; a flexible roddimensioned to fit into and be slidable in the internal lumen, and aplurality of biopsy site markers comprising a body of dehydratedgelatin, and an X-ray detectable element of specific predeterminednon-biological configuration embedded in said body of gelatin, saidbiopsy site markers being enclosed in the internal lumen, from wherethey can be pushed out with the flexible rod through the ramp-shapedopening into a biopsy site.
 14. The combination in accordance with claim13 wherein the X-ray detectable element of the biopsy site markerscomprises metal.
 15. The combination in accordance with claim 13 wherethe X-ray detectable element of the biopsy site markers comprisesstainless steel.
 16. The combination in accordance with claim 13 whereinthe X-ray detectable element of the biopsy site markers comprisesceramic materials or metal amides.
 17. The combination in accordancewith claim 13 where the biopsy site markers additionally comprise aplurality of air bubbles embedded in said body of gelatin.
 18. Thecombination in accordance with claim 13 wherein the gelatin of thebiopsy site markers has a Bloom rating in the range betweenapproximately 150 to 300 Bloom.
 19. The combination in accordance withclaim 18 wherein the gelatin of the biopsy site markers has a Bloomrating in the range between approximately 200 to 300 Bloom.
 20. Thecombination in accordance with claim 13 further comprising at least onebiopsy site marker that has a body of dehydrated gelatin, and lacks theX-ray detectable element of specific predetermined non-biologicalconfiguration embedded in said body of gelatin.
 21. The combination inaccordance with claim 20 comprising an array of a plurality of saidbiopsy site markers having said X-ray detectable element of specificpredetermined non-biological configuration and a plurality of saidbiopsy site markers having a body of dehydrated gelatin and lacking theX-ray detectable element of specific predetermined non-biologicalconfiguration, said array being enclosed in the internal lumen.
 22. Thecombination in accordance with claim 21 wherein said biopsy site markershaving said X-ray detectable element of specific predeterminednon-biological configuration and said biopsy site markers having a bodyof dehydrated gelatin and lacking the X-ray detectable element ofspecific predetermined non-biological configuration alternate in saidarray.
 23. A marker body which is deliverable to a biopsy site within apatient, comprising: a preshaped pellet formed of dehydratedbioabsorbable material having a plurality of gas bubbles dispersedtherein which are configured to facilitate ultrasonic observation of thepellet at the biopsy site within the patient, and having an X-raydetectable element of specific predetermined non-biologicalconfiguration embedded therein.